title: Oncogenic mutations in adenomatous polyposis coli (Apc) activate mechanistic target of rapamycin complex 1 (mTORC1) in mice and zebrafish.
abstract: Truncating mutations in adenomatous polyposis coli (APC) are strongly linked to colorectal cancers. APC is a negative regulator of the Wnt pathway and constitutive Wnt activation mediated by enhanced Wnt-β-catenin target gene activation is believed to be the predominant mechanism responsible for APC mutant phenotypes. However, recent evidence suggests that additional downstream effectors contribute to APC mutant phenotypes. We previously identified a mechanism in cultured human cells by which APC, acting through glycogen synthase kinase-3 (GSK-3), suppresses mTORC1, a nutrient sensor that regulates cell growth and proliferation. We hypothesized that truncating Apc mutations should activate mTORC1 in vivo and that mTORC1 plays an important role in Apc mutant phenotypes. We find that mTORC1 is strongly activated in apc mutant zebrafish and in intestinal polyps in Apc mutant mice. Furthermore, mTORC1 activation is essential downstream of APC as mTORC1 inhibition partially rescues Apc mutant phenotypes including early lethality, reduced circulation and liver hyperplasia. Importantly, combining mTORC1 and Wnt inhibition rescues defects in morphogenesis of the anterior-posterior axis that are not rescued by inhibition of either pathway alone. These data establish mTORC1 as a crucial, β-catenin independent effector of oncogenic Apc mutations and highlight the importance of mTORC1 regulation by APC during embryonic development. Our findings also suggest a new model of colorectal cancer pathogenesis in which mTORC1 is activated in parallel with Wnt/β-catenin signaling.
authors.affiliation: Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Valvezan
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.forename: Michael
authors.initials: M
authors.lastname: Pack
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D015179:Colorectal Neoplasms / Q000378:metabolism; D017491:Genes, APC; D008099:Liver / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D046912:Multiprotein Complexes; D025521:Tumor Suppressor Proteins; D029961:Zebrafish Proteins; C541913:apc protein, zebrafish; D051176:beta Catenin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: APC; Colon cancer; GSK-3; Polyposis; Wnt; Zebrafish; mTOR; mTORC1